Azilsartan, also known as 1-[[2′-(4,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl) [1,1′-biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid, is a potential angiotensin II receptor antagonist for treating hypertension by oral administration. Azilsartan has formula (I):

Azilsartan (TAK-536) is developed by Takeda Pharmaceutical Company Limited (Takeda) in Japan as an angiotensin II receptor antagonist for treating hypertension. Takeda submitted a New Drug Application in Japan on March 2011. Azilsartan can be prepared for administration in the form of a prodrug ester or salt of the prodrug ester such as Azilsartan medoxomil, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-([2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-1H-benzimidazole-7-carboxylate, potassium salt, having formula (II):

Azilsartan medoxomil was approved and listed by FDA in February 2011 for once-daily oral treatment of hypertension for adults. Azilsartan medoxomil can be used either alone or in combination with other antihypertensive agents.
Azilsartan is disclosed by Takeda in Chinese patent application CN 93100006.8 (CN 1079966 A). The method of preparation of azilsartan is disclosed in the specification of CN 93100006.8. Example 1 of CN 93100006.8 discloses that azilsartan can be synthesized in four steps. In the final step, the solvent is evaporated completely and then azilsartan is recrystallized from ethyl acetate to obtain colorless prisms of azilsartan with a melting point of 156° C. to 157° C. The synthesis of azilsartan is also disclosed in the J. Med Chem. 1996, 39, pp. 5228-5235 and Chinese Journal of Pharmaceuticals, 2010, 41(12), pp. 881-883. In the final step, azilsartan is recrystallized from anhydrous ethanol to obtain white solid azilsartan with a melting point of 190° C. to 191° C.
However, the above references do not fully characterize the azilsartan polymorphs. Therefore, we do not know the polymorphic forms of the azilsartan polymorphs disclosed in these references. There are many methods that can be used to characterize polymorphs of a drug. Single crystal X-ray diffraction is currently regarded as the most reliable evidence of a particular polymorphic form. However, X-ray powder diffraction can also be used to provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal analysis (e.g., differential scanning calorimetry, thermal gravimetric analysis and hot-stage microscopy), and spectroscopy (e.g., infrared (IR), Raman, solid-state nuclear magnetic resonance (ssNMR)), are also helpful for characterizing polymorphic forms.
A drug such as azilsartan may exist in different crystalline forms, which may have significant differences from each other in appearances, solubilities, melting points, dissolution rates, bioavailabilities, stability, efficacy and the like. However, the currently available crystalline forms of azilsartan have relatively low solubilities, bioavailabilities and/or efficacies.
Therefore, there is a need for novel crystalline forms of azilsartan having better physicochemical properties, especially, relatively higher solubilities, bioavailabilities and/or efficacies. There is also a constant need for a low cost and industrial friendly process for preparing the crystalline forms of azilsartan.